Renal transplantation provides clear benefits for patients with end stage kidney disease1,2, and significant cost savings compared to dialysis3,4. In 2010, 16,151 renal transplants were performed in the USA (http://optn.transplant.hrsa.gov), with the corresponding figure for the UK being 2,687 (http://www.uktransplant.org.uk). However, a proportion of patients experience early complications which can significantly impact the clinical and health economic outcomes, such as delayed graft function (DGF)5.
A number of definitions of DGF have been proposed6-8 with one commonly used being the need for dialysis in the first week after renal transplantation, other than for isolated hyperkalaemia. Although there are parallels with acute kidney injury seen in other clinical situations, the pathology underlying DGF is complex with contributions from donor-derived factors such as donor age and duration of ischaemia, and recipient factors such as reperfusion injury, immunological responses and immunosuppressant medications9. Acute tubular necrosis (ATN) secondary to ischaemia-reperfusion injury (IRI) is the predominant histological finding in patients with DGF, but acute cellular or humoral rejection may occur concurrently, and other pathologies are sometimes apparent histologically, e.g. calcineurin inhibitor toxicity. Increasing use of organs donated after circulatory death (DCD) and from extended criteria donors10, has corresponded with an increase in the incidence of DGF which currently affects ˜20% of transplant recipients in the USA5. DGF increases the risk of graft failure, patient death and death-censored graft failure by 2-3 fold11,12, and is associated with a number of complications that contribute to reduced longer-term graft survival, such as a poor transplant function at one year, arterial hypertension, and acute rejection13. Overall, DGF has been associated with a 41% increased risk of graft loss at just over 3 years14.
Early identification of DGF and increased understanding of the specific underlying pathology has significant potential to improve immediate patient management15, allowing fluid volume status optimisation, timely appropriate dialysis, and avoidance of unnecessary investigation and treatment. The opportunity to stratify patients and tailor specific therapeutic interventions at an earlier time point may in turn result in improved longer-term outcomes. With developments in proteomic technologies, there is increasing excitement about the potential of clinical proteomics in identifying new biomarkers with clinical impact16, complementing promising markers emerging from genomic-based studies.
Urinary markers currently under investigation as potential predictors of requirement for dialysis and graft recovery after transplantation include interleukin 18 (IL-18) and neutrophil gelatinase lipocalin (NGAL)17, with tissue-associated markers including ICAM-1 and VCAM15,18. Unfortunately, in the majority of cases of DGF, urine is not produced or may be mixed with residual native renal output confounding analysis of any results and biopsied tissue is often only available relatively late once DGF is established. Although NGAL and IL-18 have not shown promise when analysed in serum19, blood-borne biomarkers would be an ideal way of monitoring post-transplantation due to the accessibility and routine use in hospital laboratories. However, biomarker discovery with serum or plasma is challenging with only 22 proteins comprising ˜99% of the total protein mass, and the wide dynamic range of protein abundances spanning ˜10 orders of magnitude20.
As discussed above, a number of potential biomarkers have been associated with renal ischaemia-reperfusion injury, such as NGAL, IL-18, KIM-1, L-FABP, netrin-1, and keratinocyte-derived chemokine, though the majority of these have been studied in urine, and in native acute kidney injury (AKI) rather than post-transplantation in the context of DGF. Urinary NGAL and IL-18 have been examined in DGF with AUCs of 0.78 and 0.77 at 18 h post transplant. Encouraging though these results appear, they are subject to the difficulties of whether urine output occurs at all post-transplant in DGF and where such output is confounded by ongoing urine productive from native kidneys. Furthermore, whilst urinary NGAL has been proposed as a marker to distinguish pre-renal from intrinsic renal failure in AKI, and similar use in transplant patients might be imagined, its true ability to discriminate is questionable. NGAL and IL-18 have been studied in serum in DGF and SGF, but no discrimination between groups was seen, whereas Cystatin C did discriminate, outperforming serum creatinine. Donor urinary NGAL, but not serum NGAL has been associated with prolonged DGF. Despite the numerous candidates for biomarkers in IRI, and the investigations to date of promising markers like NGAL and IL-18, as yet no candidate marker in serum has emerged with clear clinical utility.
Delayed graft function remains a major clinical concern in renal transplantation, not only because of the impact on length of patient stay and associated costs, but because of the difficulty in managing patient's fluid status, and the timely, appropriate use of dialysis (especially haemodialysis) to avoid possible further clinical complications which can occur with over-zealous fluid removal from “wet” post-transplant patients who are exhibiting minimal renal function. Furthermore, the known negative longer term impact on patients who experience DGF means this is of significant importance to practicing renal transplant clinicians.
Accordingly, there remains a need for a blood-borne biomarker predictive for ischaemia-reperfusion injury, such as DGF.